In clinical examinations, the presence and quantity of substances in collected blood samples are typically assayed. Diabetics measure their own blood sugar value several times each day, and determine their insulin dosage based on the measured value so as to self-manage their blood sugar level in determining food-intake restrictions, amount of exercise, and the like. Normally, the measurement of a blood sugar value is taken from blood samples collected using a puncturing tool or the like, which causes physical discomfort and burden for the patient. From this perspective, a simple examination that neither overburdens the patient nor requires blood collection would be very desirable.
In response to this demand, methods have been developed for extracting analyte in living tissue noninvasively and without collecting blood, and for measuring the amount and concentration of the analyte. Reverse iontophoresis is an example of such an assay method.
Reverse iontophoresis involves extracting an analyte through the skin by applying electrical energy to the skin (for example, see: U.S. Pat. No. 5,279,543 and International Patent Publication No. 96/000110).
Assay methods and devices using reverse iontophoresis have certain disadvantages, however, inasmuch as the quantity of extracted analyte is not stable until a lengthy time has elapsed after the initial application of electrical energy on the skin (i.e., start of current flow). For example, a Gluco Watch from Cygnus Incorporated requires that the device be installed approximately 3 hours before starting the actual measurement in order for the device to attain a state of equilibrium.
The results of diligent research by the inventors of the present application, and investigation of the causes of the long-term instability of the analyte extraction amount are described below.
FIG. 1 illustrates the internal structure of a conventional extraction device. An extraction device 1 includes a positive polarity chamber 11, negative polarity chamber 14, positive electrode 12, negative electrode 15, collection materials 13 and 16, and power supply 17. Reference number 18 refers to the skin of a subject, and reference number 20 refers to the internal area of living tissue. The positive polarity chamber 11 and negative polarity chamber 14 are placed on the skin 18. The positive electrode 12 and collection material 13 are accommodated within the positive polarity chamber 11, and the negative electrode 15 and collection material 16 are accommodated in the negative polarity chamber 14. The positive electrode 12 and negative electrode 15 are connected to the power supply 17. The power supply 17 is a constant-current power supply.
When the power supply 17 starts supplying a current, the extraction device 1 forms the electrical circuit shown in FIG. 2. In the drawing, the electrical resistance value of the skin 18 is designated Rep, and the electrical resistance value in the living tissue 20 is designated Rsub.
The condition of the skin 18 after current flow begins via the power supply 17 is described below with reference to FIG. 3, which shows an enlargement of the area 22 of FIG. 2. FIG. 3 illustrates the state of the area 22 after a predetermined time has elapsed following the start of current flow.
An analyte transmission path 24 is formed in the skin 18 via the application of electrical energy from the power supply 17. This analyte transmission path is formed by the enlargement of macropores such as sweat glands, pores and the like, and intercellular micropores via the application of a predetermined energy to the skin, and allows the transmission of analyte within the path. The analyte transmission path is formed more easily with the application of greater energy. The analyte transmission path has a smaller electrical resistance than the other regions of the skin.
The electrical resistance value Rep1 of the analyte transmission path 24 is smaller than the electrical resistance Rep2 of the region outside the analyte transmission path 24 (Rep1<Rep2), and these resistance values are expressed in equation (1) below.1/Rep=1/Rep1+1/Rep2  (1)
When the current flowing through the analyte transmission path 24 is designated Iep1, and the current flowing through the region outside the analyte transmission path 24 is designated Iep2, the equation (2) shown below can be derived.Iep1×Rep1=Iep2×Rep2  (2)
Since the value Rep1 is less than Rep2, the relationship Iep1>Iep2 can be derived from equation (2). That is, although a large current flows in the analyte transmission path 24, a smaller current flows in the region outside the analyte current path. From another perspective, the current is concentrated in the analyte transmission path 24. This means that most of the electrical energy from the power supply 17 is supplied to the analyte transmission path 24, and a lesser amount of electrical energy is supplied to the region in which the analyte transmission path is not yet formed. Accordingly, the analyte transmission path has difficulty forming in the region in which the analyte transmission path is not yet formed, and a long time is required until the path is formed.
When current is flowing continuously after the state shown in FIG. 3 has been attained, the analyte transmission paths are gradually formed even in the region in which the analyte transmission path was not originally formed, and the number of analyte transmission paths becomes constant at a specific time T1 (refer to FIG. 4). The condition of the skin at time T1 is shown in FIG. 5. When at least a predetermined number of analyte transmission paths have been formed, as shown in FIG. 5, the number of analyte transmission paths is stabilized, and a stable amount of analyte can be extracted. However, the conventional extraction device requires a long time (T1) until the analyte transmission paths are formed and the amount of extracted analyte becomes stable because the current is concentrated in only some of the analyte transmission paths.
In view of the above-described circumstances, the present invention provides extraction devices, analyzers, extraction methods and analysis methods which can reduce the waiting time prior to the extraction of the analyte.